Project Summary/Abstract There is a wealth of evidence indicating that vascular dysfunction is a prominent contributor to the development of Alzheimer's disease (AD). Pathological changes in vessel hemodynamics, angiogenesis, blood-brain barrier permeability and immune cell migration in AD have been attributed to the vasculotoxic effects of amyloid-? (A?) plaques, and more recently, tau, with animal studies suggesting that A? and tau lead to blood vessel abnormalities and blood-brain barrier breakdown. On the other hand, alterations in brain perfusion are known to be present long before the clinical symptoms of AD develop, perhaps even preceding amyloid-? (A?) plaque accumulation, tau deposition, and brain atrophy. It is critical to understand how vascular dysfunction develops early in AD and how it relates to the classical AD biomarkers of A? and tau in order to develop a reliable and accurate cerebrovascular biomarker of AD that can be used to identify AD in the early asymptomatic stages of disease. Imaging studies have shown that capillary dysfunction correlates to the severity of AD and cerebral blood flow (CBF) decreases in adults at risk for AD and in AD animal models. These findings support the importance of quantification of vascular changes as it may provide a more comprehensive and possibly more sensitive marker for detecting early AD changes. Recent studies in mice that develop either tangles or plaques uncovered surprising evidence of morphological and functional alterations in the capillaries. In vivo two-photon microscopy in these mice revealed tortuous capillaries with diminished blood flow, and the vessels showed specific RNA signatures of angiogenesis and inflammation. Additional studies within the last year have confirmed analogous microvascular and RNA changes in patients with AD, consistent with the hypothesis that microvascular pathology is critical in mediating the development of AD. Thus, although it is commonly assumed that reduced CBF is secondary to neuronal loss, we postulate that neuronal loss may be due to AD- induced vascular abnormalities. In this exploratory study, we propose to investigate imaging biomarkers for cerebrovascular alterations, by using cutting-edge perfusion magnetic resonance imaging (MRI) techniques, in individuals with known levels of A? and tau protein as quantified through PET. The study design will build on our preliminary work using advanced MRI techniques to probe cerebrovascular function together with high-sensitivity PET imaging markers of A? and tau in patients with AD and cognitively healthy older adults at risk for developing AD. We expect to identify the most promising cerebrovascular imaging biomarkers that are sensitive and specific to the cerebrovascular alterations that occur in AD in its early stages. Once identified, these imaging markers can be leveraged for defining the temporal sequence of events and relationships between abnormal protein deposition and cerebrovascular impairment in a large longitudinal study in the near future.